Inhibition of the Canonical IKK/NFκB Pathway Sensitizes Human Cancer Cells to Doxorubicin

Abstract

The NFκB family is composed by five subunits (p65/RelA, c-Rel, RelB, p105-p50/ NFκB 1 , p100-p52/NFκB 2 ) and controls the expression of many genes that participate in cell cycle, apoptosis, and other key cellular processes. In a canonical pathway, NFκB activation depends on the IKK complex activity, which is formed by three subunits (IKKa and IKKb and IKKg/NEMO). There is an alternative NFκB activation pathway that does not require IKKb or IKKg/NEMO, in which RelB is a major player. We report in a panel of human breast cancer cells that the IKK/NFκB system is generally overexpressed in breast cancer cells and there is heterogeneity in expression levels of individual members between different cell lines. Doxorubicin, an anticancer agent used in patients with breast cancer, activated NFκB and appeared to be less effective in cells expressing predominantly members of the canonical IKK/NFκB. Two NFκB inhibitors, bortezomib and NEMO-Binding Domain Inhibitory Peptide, prevented doxorubicin-induced NFκB activation and increased doxorubicin antitumor effects in BT-474 cells. Transient down-regulation of members of the canonical pathway (p65, p52, c-Rel and IKKg/ NEMO) by siRNA in HeLa cells increased doxorubicin cytotoxicity. In contrast, silencing of RelB, a key subunit of the alternative pathway, had no evident effects on doxorubicin cytotoxicity. To conclude, NFκB inhibition sensitized cells to doxorubicin, implying directly p65, p52, c-Rel and IKKg/NEMO subunits in chemoresistance, but not RelB. These findings suggest that selective inhibition of the canonical NFκB pathway is sufficient to improve doxorubicin antitumor effects.

Cancer Stem Cells in Prostate Cancer: Implications for Targeted Therapy

“…The NF-κB pathway is upregulated in CSCs and is important for apoptosis resistance in tumor cells [35,48,77,81] . It has been shown that the activation of NF-κB signaling in PCa cells correlates with PCa progression, chemoresistance, recurrence, and metastasis [82,83] .…”

Epithelial-mesenchymal transition and drug resistance in breast cancer (Review)

“…Constitutively active NF-κB was also discovered to play a key role in resistance to death-inducing stimuli, including chemotherapeutic agents (53). NF-κb inhibitors were found to sensitize breast cancer cells to doxorubicin (54). previous studies also showed that phosphorylation and overexpression of NF-κB caused an increase in ER-mediated transcription associated with endocrine resistance.…”

Phosphorylation of IκBα at Serine 32 by T-lymphokine-activated Killer Cell-originated Protein Kinase Is Essential for Chemoresistance against Doxorubicin in Cervical Cancer Cells

“…has been suggested to induce IB phosphorylation and p65 nuclear translocation (28). To clarify the effect of TOPK on doxorubicin-mediated IB␣ degradation or phosphorylation, we employed HeLa-TOPK siRNA knockdown cell lines.…”